C-reactive protein (CRP) is a normal plasma protein of the pentraxin protein family, the other member of which is the very closely similar molecule, serum amyloid P component (SAP)(1). CRP is the classical acute phase protein, the circulating concentration of which increases dramatically in response to most forms of inflammation, tissue injury and infection, and the value attained in most conditions correlates closely with the extent and activity of disease(2). CRP is a calcium dependent ligand binding protein, the ligand which it binds with highest affinity being phosphocholine residues(3), but it also binds a variety of other ligands. It binds many of its ligands with high avidity. Known ligands for CRP include both autologous and extrinsic structures. Autologous ligands include native(4,5) and modified plasma lipoproteins, damaged cell membranes (6), a number of different phospholipids and related compounds(7), and small nuclear ribonucleoprotein particles(8,9). Extrinsic ligands include many glycan, phospholipid and other components of micro-organisms, such as capsular and somatic components of bacteria, fungi and parasites, as well as plant products(10-15). When CRP has bound to its ligands it becomes capable of activating complement by the classical pathway via Clq(16-19) and achieving activation and fixation of C3, the main adhesion molecule of the complement system(20,21), as well as engagement of the terminal lytic phase, C5-C9(22).
Whilst very early clinical work(23) suggested that CRP might possibly contribute to inflammation, and subsequent experimental animal studies were interpreted as showing a pro-inflammatory role for CRP, there has until lately been no direct evidence of any involvement of CRP in processes of inflammation and tissue damage. There are a few reports of CRP deposition in inflammatory and necrotic tissue lesions, and of association between CRP and complement activation(24-30). However none of these studies shows directly that CRP is responsible for tissue damage, and the only study of real time CRP deposition in human tissues in living patients showed that it occurred only in trace amounts, if at all(31). Indeed the published work that directly examines the role of CRP in experimental models of disease indicates that CRP may have an anti-inflammatory role that down-regulates infiltration of inflammatory cells and reduces tissue damage(32,33). This would be consistent with the finding that complexed CRP is relatively inefficient at generating the terminal phase of complement activation and that involvement of CRP down-regulates other potentially inflammatory aspects of complement activation(34,35). Very recent work in different models involving handling of apoptotic cells also indicates that CRP has anti-inflammatory properties(36). There is thus certainly no consensus about the role of CRP in vivo and the predominant view is that it may be anti-inflammatory. In general the association of increased CRP production with disease conditions has hitherto been interpreted on the basis that CRP production reflects the severity of the underlying disease and/or the presence of intercurrent complications. However we have lately demonstrated unequivocally that CRP can exacerbate ischaemic tissue damage in vivo, via a complement dependent mechanism, and established that inhibition of CRP binding in vivo is a potentially important therapeutic goal (37). This is the subject of U.S. patent application Ser. No. 0119370.5, the contents of which are hereby incorporated by reference.
Atherosclerosis is extremely prevalent in developed countries and its major complications of myocardial infarction and stroke together account for about one third of all deaths. Although there have been advances in understanding of some aspects of pathogenesis and in prophylactic and post-event salvage treatments, the personal, social and economic burden of these conditions remains enormous. Similarly, chronic inflammatory diseases of unknown aetiology are common, debilitating, expensive and often dangerous to treat symptomatically, as well as being incurable and often shortening life expectancy. For example, rheumatoid arthritis affects about 4% of the population over the age of 50 years and, as well as being painful and causing severe disability, it is associated with significant premature mortality. The cancer burden is very heavy, accounting for about one third of all deaths in developed countries, and the severity and importance of infectious disease throughout the world is evident. There is a pressing need for new drugs to reduce severity and to prolong survival in all these different conditions.